Spleen Tyrosine Kinase (Syk), which is a non-receptor type intracellular tyrosine kinase, plays essential roles for activation of B cells and in an intracellular signaling system mediated by an Fc receptor. For example, Syk is associated with a FcεRI signal that is an immunoglobulin E receptor in mast cells, basophils and other cells, and thus it regulates generation of inflammatory mediators such as histamine or leukotrien, as well as cytokine, from these cells. At the same time, Syk plays a role in transmitting activation signals caused by stimulation of Fcγ receptor into monocytes, dendritic cells and other cells (Non Patent Documents 1 and 2). Moreover, it has been reported that Syk is also associated with cytokine signaling caused by integrin, IL-13, IL-15 and the like (Non Patent Documents 3 and 4).
In the case of a B-cell, a signal is transmitted into the cell mediated by a BCR (B-cell antigen receptor) expressed on the cell membrane, so that activation and differentiation of the cell is induced, resulting in generation of an antibody. It has been reported that Syk is essential for such an activation and differentiation process (Non Patent Document 5).
It is anticipated that it is possible to suppress various cell responses by inhibiting Syk (Non Patent Documents 5 and 6).
In the case of a type I allergy, which is an immediate-type allergy reaction, for example, immunoglobulin E (IgE) binds to FcεRI, which is a high-affinity IgE receptor, and an allergen then binds thereto to promote activation of the FcεRI and the release of inflammatory mediator. As a result, allergic symptoms are expressed. It is anticipated that inhibition of Syk activity will lead to the suppression of the activation of the FcεRI, and that it will be useful for the treatment of representative type I allergy-related diseases such as bronchial asthma, allergic rhinitis, hives, and atopic dermatitis.
Moreover, it is considered that inhibition of Syk activity leads to the suppression of the activation and/or maturation of immune B cells and the generation of antibodies, and that such inhibition of Syk activity can also regulate immune reactions other than type I allergy. Accordingly, it is also anticipated that inhibition of Syk activity will be effective for autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.), autoimmune hemolytic anemia, nephrotic syndrome, contact dermatitis, and the like. Furthermore, since inhibition of Syk activity also leads to the suppression of the activation of macrophages, it is anticipated that inhibition of Syk will be also effective for idiopathic thrombocytopenic purpura.
Further, inhibition of Syk activity suppresses not only immune and/or inflammatory diseases, but also activation and proliferation of lymphocytes, including B-cells as typical examples. Thus, it is anticipated that inhibition of Syk will be also effective for the treatment of various types of proliferative diseases such as lymphoma and lymphocytic leukemia. Still further, since inhibition of Syk activity regulates proliferation and differentiation of bone marrow cells, it is anticipated that it will be also effective for acute myelocytic leukemia.
On the other hand, Syk has been known to be involved in signaling mediated by integrin which is a cell adhesion molecule. Since Syk is expressed in blood platelets and is involved in the activation thereof, an inhibitor of such Syk is anticipated to be effective as a therapeutic agent for diseases associated with the activation of blood platelets.
A large number of compounds having Syk-inhibitory activity have been reported (Patent Documents 1 to 4). In clinical tests in which rheumatoid arthritis and idiopathic thrombocytopenic purpura have been targeted, useful compounds (Non Patent Document 7) and compounds having Syk and/or JAK inhibitory activity (Patent Documents 5 to 8) have been reported.